Prognostic value of new left atrial volume index severity ...
嚜燉azzeroni et al. Cardiovascular Ultrasound (2016) 14:35
DOI 10.1186/s12947-016-0077-0
RESEARCH
Open Access
Prognostic value of new left atrial volume
index severity partition cutoffs after cardiac
rehabilitation program in patients
undergoing cardiac surgery
Davide Lazzeroni1*, Nicola Gaibazzi2, Matteo Bini3, Giacomo Bussolati1, Umberto Camaiora1, Roberto Cassi1,
Simone Geroldi1, Pietro Tito Ugolotti1, Lorenzo Brambilla1, Valerio Brambilla1, Paolo Castiglioni4 and Paolo Coruzzi3
Abstract
Background: Previous studies showed that left atrial enlargement is an independent marker of adverse outcomes in
both primary and secondary cardiovascular prevention. However, no data are available on long-term outcomes in
patients undergoing valve surgery and/or coronary artery by-pass graft (CABG) surgery. Aim of the study was to
evaluate long-term prognostic role of left atrial volume index (LAVi) after cardiac surgery, using the cutoff values
recently proposed by the European Association of Cardiovascular Imaging and American Society of Echocardiography.
Methods: We created a retrospective registry of 1703 consecutive patients who underwent cardiovascular
rehabilitation program after cardiac surgery, including CABG, valve surgery and valve + CABG surgery. LAVi was
calculated as ratio of left atrium volume to body surface area, in ml/m2 at discharge; 563 patients with available LAVi
data were included in the study.
Results: In the whole population LAVi was 36 ㊣ 14 ml/m2 (mean ㊣ SD) and the follow-up time was 5 ㊣ 1.
5 years. Increased LAVi (>34 ml/m2) predicted major adverse cardiovascular and cerebrovascular events
(MACCEs) (HR = 2.1; CI95 %: 1.4每3.1; p < 0.001) and cardiovascular mortality (HR = 2.2; CI95 %: 1.0每4.5; p = 0.032).
An increased LAVi remained MACCEs predictor after adjustement for age, gender, diabetes, atrial fibrillation at
discharge, echocardiographic E/A ratio and left ventricular ejection fraction (HR = 1.8; CI95 %: 1.0每3.0; p = 0.
036). When the study population was split according to increasing LAVi values, left atrium enlargement
resulted a predictor of progressively worse adverse outcome.
Conclusions: LAVi is a predictor of long-term adverse cardiovascular outcome after cardiac surgery, even after
correction for main clinical and echocardiographic variables. The recently recommended LAVi severity cutoffs
appear adequate to effectively stratify outcome in patients undergoing rehabilitation after cardiac surgery.
Keywords: Left atrial volume index, Coronary artery by-pass graft, Cardiac valve surgery, Echocardiography,
cardiovascular outcomes
Abbreviations: ACS, Acute coronary syndrome; CABG, Coronary artery by-pass graft; CRP, Cardiac
rehabilitation program; E/A, Ratio of the early to late ventricular filling velocities; EF, Ejection fraction;
HF, Heart failure; LA, Left atrium; LAVi, Left atrial volume index; LV, Left ventricle; MACCEs, Major adverse
cardiovascular and cerebrovascular events; MI, Myocardial infarction
* Correspondence: davide.lazzeroni@
1
Fondazione Don Carlo Gnocchi, University of Parma, Fondazione Don
Gnocchi, Piazzale dei servi n∼ 3, 43121 Parma, Italy
Full list of author information is available at the end of the article
? 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
() applies to the data made available in this article, unless otherwise stated.
Lazzeroni et al. Cardiovascular Ultrasound (2016) 14:35
Background
Left atrium (LA) modulates left ventricular (LV) filling
and cardiovascular performance by functioning as a reservoir and a conduit for pulmonary venous return and as a
※booster§ that augments ventricular filling during late ventricular diastole. LA also reflects LV filling pressure and is
capable of remodeling (enlarging) in response to its elevation [1, 2]. Although there is a growing body of evidence
demonstrating that LA enlargement is an independent
marker of adverse outcomes both in primary [3每7] and
secondary [8每11] cardiovascular prevention, to date, there
are no published data assessing long-term outcome in patients undergoing valve and coronary artery by-pass graft
(CABG) surgery.
Aim of this retrospective study was to examine longterm prognostic implications of left atrial volume index
(LAVi) assessment in patients undergoing cardiovascular
rehabilitation program (CRP) after cardiac surgery, using
the cutoff values proposed by the recently-published
guidelines of the European Association of Cardiovascular Imaging (EACVI) and American Society of Echocardiography (ASE) [12].
Methods
Patients* selection
We created a registry of consecutive patients undergoing
cardiovascular rehabilitation program (CRP) after cardiac
surgery, including CABG, valve surgery and combined
valve and CABG surgery, from January 2007 to June 2012.
A total of 1703 subjects (70 % men, mean age of 69 ㊣
11 years) were collected and, out of them, all 563 patients
with available biplane left atrial volume data were extracted
for the current analysis. The internal review board of Fondazione Don Gnocchi approved data collection. All patients completed a standard in-hospital CRP, lasting
approximately 2 weeks, consisting of supervised exercise
sessions (120 min per day), lifestyle and risk factor management, medical counseling and medical therapy
optimization. For each patient we collected variables from
medical record including anamnestic and demographic
findings, clinical and laboratory markers, electrocardiographic and echocardiographic measurements, physical
activity data, pharmacological therapy adherence. Outcomes were collected through a telephonic questionnaire
administered by a medical doctor or a supervised fellow
and all patients provided oral informed consent. End
points were: overall mortality and major adverse cardiovascular and cerebrovascular events (MACCEs) defined as either: cardiovascular (CV) mortality, non-fatal acute
coronary syndrome (ACS), heart failure (HF) and stroke.
Echocardiographic data
M-mode and 2-dimensional echocardiographic images
were obtained with a commercially available
Page 2 of 7
echocardiography machine (Esaote MyLab? 60). LA
volume was calculated using the biplane area-length
method at discharge of CRP [12]. Measurements were
obtained in end-systole from the frame preceding mitral valve opening. LAVi was calculated as the ratio of
LA volume to body surface area (ml/m2). In agreement with ASE and EACVI guidelines, we assumed
LAVi > 34 ml/m2 as the LA enlargement threshold
and we further classified LAVi values from 35 to
41 ml/ m2 as mild LA enlargement, from 42 to
48 ml/ m2 as moderate LA enlargement and greater
than 48 ml/ m2 as severe enlargement [12].
Statistical analysis
Continuous variables were expressed as mean (M) and
standard deviation (SD), categorical variables as number
(N) and percentage (%). The Student 2-sample t test,
Pearson 聿2 test, Mann每Whitney每Wilcoxon rank-sum
test were used to compare the differences between
groups for continuous, categorical and ordinal variables,
respectively. Cox proportional hazard regression analysis
was performed to create survival-free-from-event curves.
Multivariate Cox regression analysis was used to create
adjustment of hazard ratio (HR) for age, left ventricular
ejection fraction (LVEF), gender, diabetes, and ratio of
the early (E) to late (A) ventricular filling velocities (E/A
ratio). Event-free survival analysis was measured from
admission to the first event. Significance was defined as
a p value 34 ml/m2)
N = 306
N = 257
Age (years)
68 (10)
71 (9)**
Male sex
245 (61)
154 (39)**
BMI (kg/m2)
26.9 (4)
26.7 (4)
BSA (m2)
1.9 (0.2)
1.8 (0.2)**
CV risk Factors
Familiar history (CVD)
159 (56)
120 (44)
AHT
159 (52)
146 (48)
DM
83 (55)
66 (45)
Dyslipidaemia
165 (57)
120 (43)
197 (75)
95 (25)**
Types of cardiac surgery
CABG
Heart-valve surgery
73 (25)
118 (75)**
CABG + Valve surgery
37 (46)
43 (54)
ACS
116 (63)
68 (37)*
Stable Angina
66 (67)
32 (33)*
MV Stenosis
2 (22)
7 (78)
Clinical indications
MV regurgitation
44 (44)
56 (56)*
End point
AV Stenosis
23 (32)
20 (68)**
Mean follow-up was 5 ㊣ 1.5 years. All-cause mortality
consisted in 55 deaths (10 %) and the total amount of
MACCEs was 114 (20 %), composed by 31 CV deaths
(5 %), 43 HF hospitalization (8 %), 15 strokes (3 %) and
25 ACS (4 %).
MACCEs were 2.1-fold higher in patients with LAVi >
34 ml/m2 compared with patients with normal LA volume, this difference being significant even considering
patients who received CABG or valve surgery separately
(in particular in patients with mitral and aortic regurgitation; see Table 2). Moreover, event-free survival from
MACCEs was significantly lower in both patients who
underwent CABG and valve surgery with enlarged LA
(Fig. 1).
By dividing the whole population according to severity partition cut-offs, MACCEs rate was significantly higher in patients with either moderate or
severe LA enlargement but not in those with mild
LA enlargement (Fig. 2 and Table 2). Multivariate
analysis, adjusted for age, gender, diabetes, E/A, atrial
fibrillation at discharge and LVEF, confirmed the role
of LA enlargement in predicting MACCEs in the
whole population; moreover, the progressive increase
of LAVi severity maintained an incremental risk of
MACCEs in patients with LA enlargement ranging
from moderate to severe (Fig. 3).
Severe LA enlargement resulted a significant and robust predictor of any type of secondary end point: all-
AV regurgitation
19 (46)
22 (54)
Other indication
36 (62)
22 (38)
LAV (ml)
49 (11)
85 (22)**
LAd (mm)
38 (5)
54 (6)**
LVEF (%)
52 (9)
49 (10)*
LV EDV (ml)
105 (41)
108 (42)
IVS (mm)
12 (2)
13 (2)**
E/A Ratio
1 (0.4)
1 (0.6)
Echocardiographic parameters
Medications
汕-Blocker
201 (52)
185 (48)
Amiodarone
79 (51)
77 (49)
OAT
72 (38)
117 (62)**
ACEi
216 (57)
170 (43)**
Statins
218 (56)
168 (44)**
Values are expressed as mean and standard deviation or as number
and percentage
LA left atrium; LAVi left atrial volume index; BMI body mass index; CVD
cardiovascular disease; AHT arterial hypertension; DM diabetes mellitus; CABG
coronary artery bypass graft; ACS acute coronary syndrome; MV mitral valve;
AV aortic valve; Lad left atrium antero-posteior diameter; LVEF left ventricular
ejection fraction; IVSs interventricular septum; LV EDV left ventricular enddiastolic volume; OAT oral anticoagulant therapy
*and **indicate differences at significance levels p 34 ml/m2. Event-free survival
from cardiovascular mortality was significantly lower
in these patients (Fig. 4), whilst only a trend towards
a higher all-cause mortality was found in patients
with LAVi > 34 ml/m2 (Table 2).
Discussion
The present study demonstrates, in a population of
563 patients followed for about 5 years after cardiac
surgery, that post-operative LAVi is a long-term predictor of MACCEs and CV mortality, also confirming
its prognostic value in predicting MACCEs even after
adjustment for age, gender, diabetes, atrial fibrillation
at discharge, E/A diastolic index and LVEF.
Left atrium reflects left ventricular filling pressure, a
parameter conditioned by structural and functional
heart impairement [1, 2]. Consequentely, LA enlargement is an echocardiographic marker that mirrors left
ventricular systolic and/or diastolic chronic dysfunction, representing a possible pathophysiological explanation of our results.
Previous studies in patients undergoing cardiac surgery only examined the relationship between LA volume and prevalence of either post-operative atrial
fibrillation [13] or symptomatic improvement of HF
Fig. 1 Left: LA enlargement and survival free from MACCEs in CABG patients. Right: LA enlargement and survival free from MACCEs in valve surgery
patients. MACCEs, major adverse cardiovascular and cerebrovascular events; LA, left atrium
Lazzeroni et al. Cardiovascular Ultrasound (2016) 14:35
Fig. 2 MACCEs and LA severity partition cut-offs after cardiac surgery.
MACCEs, major adverse cardiovascular and cerebrovascular events; LA,
left atrium
[14]. Therefore, our results offer novel data highlighting a
significant prognostic role of LAVi on MACCEs and CV
mortality in such patients. In addition, our study represents a convincing validation of the prognostic significance of the new severity partition cutoffs, suggested by
Fig. 3 Hazard Ratio with 95 % CI for MACCEs calculated after
adjustment for age, LVEF, gender, diabetes, atrial fibrillation at discharge
and E/A ratio, in subgroups of patients with mild, moderate and severe
LA enlargement, and in all patients with LA enlargement; * and **
indicate significant differences from HR = 1 at p < 0.05 and p < 0.01
significance levels
Page 5 of 7
both EACVI and ASE [12], in patients undergoing cardiac
surgery. In particular, we showed that moderate and severe LA enlargement is associated with increased rate of
MACCEs, while mildly increased LAVi represents a grey
zone which does not appear to robustly impact the
prognosis.
LA size is a recognized prognostic predictor in primary CV prevention. This was demonstrated in a 8year follow-up of 5209 individuals included in the
Framingham Heart Study, where an increased LA
diameter was associated with higher risk of stroke
and mortality [15] and other primary prevention studies suggested the independent role of LAVi in predicting CV death [3, 5, 7], MACCEs [5, 7], ischemic
stroke [6] and atrial fibrillation [4].
The prognostic significance of LAVi has been confirmed also in secondary CV prevention, especially in
patients after acute myocardial infarction (MI). An increased LA volume, assessed within the first 48 h of
admission, independently predicted 5-year mortality in
a population of 395 MI patients [8]. Similarly, LAVi
>32 ml/m2 did result an independent predictor of
mortality during a mean follow-up of 15 months in
314 MI patients [16], being these results thereafter
confirmed in a population of 610 subjects with highrisk MI followed for a mean of 20 months [9]. The
relationship between LAVi and CV outcomes was also
addressed in 935 outpatients with established coronary artery disease followed for about 4 years, concluding that
LAVi was similar to LVEF in predicting mortality and HF
hospitalization [17].
The prognostic implications of LA size were confirmed also in patients with valve disease, who did or
did not undergo cardiac surgery. Neverthless, the majority of these studies has been mainly focused on
post-operative atrial fibrillation [13, 18, 19], LVEF recovery [20] and HF symptoms [14], while harder endpoints, such as cardiovascular mortality, had only
been evaluated in 176 patients with symptomatic
chronic mitral regurgitation undergoing valve replacement by using pre-operative LA diameter [21].
Given that in previous studies the predictive significance of LA size was invariably investigated measuring LA diameter or LAVi with either arbitrary or
single cutoff value, our study could represent the first
prognostic validation of the new three cutoffs of severity partition, recently recommended by both
EACVI and ASE. Our results highlight the importance to quantify the LA size in terms of LAVi; they
also suggest that LAVi should be measured not only
in routine clinical practice but also in a rehabilitation
setting for more accurate risk-stratification and
clinical decision making in patients who underwent
cardiac surgery.
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